This project is designed to identify genetic variants that confer susceptibility to common forms of epilepsy including i) forms of idiopathic generalized epilepsy (IGE) such as juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE) and idiopathic epilepsy not otherwise specified (IGE-NOS) and ii) forms of localized epilepsy including temporal lobe epilepsy (TLE) and cryptogenic focal epilepsy (CFE). The overall strategy involves a whole genome association (WGA) study design with replication, fine-mapping and DNA re- sequencing. It is organized into four Specific Aims, each of which addresses hypotheses regarding the relationship between genetic variation and susceptibility to epilepsy. The key components of the project are i) a high-throughput genotyping platform (Illumina HumanHap 610Q BeadChip) for analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs);ii) an existing cohort of well-characterized Caucasian (CA) epilepsy patients (N ~ 1560) and a large collection of matched normal control individuals (N ~ 4000) already genotyped;iii) a series of parent-child trios from this cohort (N ~ 400);iv) a smaller number of African American (AA) epilepsy patients from this cohort (N ~ 125);v) a clinical network in place to collect a replication cohort of CA epilepsy patients (N ~ 1000) as well as an additional series of AA epilepsy patients (N ~ 125) that will be combined with those already available for comparison with an AA control cohort (N ~ 3000) also previously genotyped. The project will be carried out in 4 stages. Stage 1 will involve completion of a WGA study on ~2000 epilepsy patients with identification of genetic variants that associate with epilepsy. Data analysis will evaluate SNPs, SNP haplotypes and CNVs. Stage 2 will involve use of a customized BeadChip to analyze specifically the top 1% of SNPs (6,000) that are prioritized from Stage 1 in the replication cohort of CA epilepsy patients and in the parent-child trios to confirm and extend initial findings (~30,000 SNPs will be typed for refinement of respective loci). In parallel, while the collection of the replication cohort progresses, validation and confirmation of initial stage 1 findings will be performed using Taqman based assays in the existing family trios. Stage 3 will involve study of AA epilepsy patients (N ~ 250) with emphasis on variants identified as important in Stages 1 and 2. The smaller blocks of genomic linkage disequilibrium in AA individuals will facilitate fine-mapping. Finally, in stage 4, we will re-sequence up to 3 of the most significant and biologically relevant candidate genes in a panel of epilepsy patients (N = 100) and controls (N = 100). Overall we believe that this strategy has a high likelihood of identifying genetic variation that defines susceptibility to epilepsy. In summary, this project represents collaboration between clinical and basic scientists focused on identifying the genetic variants that confer susceptibility to common forms of epilepsy. It is unique in that it involves a combination of existing resources and expertise which will have a synergistic effect to propel the work forward and lead to important new discoveries relevant to diagnosis, treatment and ultimately a cure. PUBLIC HEALTH RELEVANCE: Untreated epilepsy particularly in more severe cases has a detrimental effect with respect to disease progression, disability and increased mortality. Epilepsy affects about 1 in 100 children, including all ethnic groups and both sexes. Epilepsy is among the most common cause of disability in children and the etiology of epilepsy remains unknown but a genetic component has been implicated from twin and family studies. This project proposes to study genetic variants that influence the pathogenesis of epilepsy in two large and independent cohorts by conducting a genome-wide association study using a high density tag-SNP platform.